The regulation of mucosal immune responses is poorly understood but characterized by a series of unusual phenomena such as oral tolerance, atypical lymphocyte populations (IEL and LPL), and chronic controlled inflammation. Thus one of the hallmarks of mucosal immunity is suppression. Our laboratory has studied the mechanisms involved in the generation of suppression in the gut and have identified a potential regulatory cell in this system, the intestinal epithelial cell. This cell expresses class I and class II MHC molecules but, unlike conventional antigen presenting cells (APCs), selectively activates CD8+ suppressor T cells in Ag specific and alloreactive systems. During the past granting period we have shown that the CD8 molecule itself is important in this activation process. Binding to CD8 activates the src-like tyrosine kinase p56/lck which in turn phosphorylates a number of intracellular proteins involved in signal transduction. The epithelial cell surface Ag which binds to CD8 is not its conventional ligand, class I, but rather appears to be a novel ligand, potentially identified by two mAbs B9 and L12, which either represent a novel restriction element or a mucosa specific adhesion molecule. This proposal seeks to further define the signaling events that occur along with the cell surface molecules involved. Specifically we will: 1. Identify the cellular interactions involved in and consequences of p56/1ck activation; determining the role of other surface proteins in this process [i.e. signaling molecules (CD2, IL2R), adhesion molecules (HML-1, VLA-4, and tyrosine phosphatases (CD45)]; addressing more physiologic interactions (IEL, LPL with IEC); and assessing the role of other anti-phosphotyrosine precipitated bands and lck associated proteins,.. and 2. Identify restriction elements and adhesion molecules involved in T cell:IEC proliferation. To this end, first, we will determine the cDNA sequence of the surface glycoproteins recognized by mAbs B9 and L12. We will also continue to study the role of nonclassical class I molecules such as CD1d or mucosal adhesion molecules (e.g. HML-1) in this process.